Methods of stabilizing azithromycin

ABSTRACT

A method of packaging of azithromycin which provides improved stability of azithromycin upon storage. Additionally, compositions and methods of stabilizing azithromycin compositions are described. Stabilized azithromycin compositions comprise an intimate admixture of azithromycin and a stabilizing-effective amount of an antioxidant to improve the resistance of the azithromycin to degradation. Coprecipitation or co-milling of azithromycin and an antioxidant are particularly preferred means of achieving an intimate admixture. Pharmaceutical formulations comprising a stabilized azithromycin composition and methods of making such formulations are also described.

RELATED APPLICATIONS

This application is a continuation in part of U.S. application Ser. No.10/782,047, filed Feb. 19, 2004, which claims the benefit of priority toU.S. provisional application Ser. No. 60/448,946, filed Feb. 19, 2003,herein incorporated by reference. This application is also acontinuation in part of U.S. application Ser. No. 10/936,075, filed Sep.7, 2004, which is a continuation of U.S. application Ser. No.10/822,773, filed Apr. 13, 2004, which is a continuation of U.S.application Ser. No. 10/247,097, filed Oct. 18, 2002, which claims thebenefit of priority to U.S. provisional application Ser. Nos.60/336,346, filed Oct. 18, 2001; 60/331,931, filed Nov. 21, 2001; and60/341,295, filed Dec. 17, 2001, herein incorporated by reference.

FIELD OF THE INVENTION

The invention encompasses methods of packaging azithromycin to preventthe degradation of azithromycin upon storage. The invention also relatesto stabilized azithromycin compositions, methods of preparing stabilizedazithromycin compositions, pharmaceutical formulations containing thestabilized azithromycin compositions and methods of making suchformulations.

BACKGROUND OF THE INVENTION

Azithromycin has the chemical name[2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-oneand the following chemical structure:

Azithromycin is one of the macrolide antibiotics, so named because theycontain a many-membered lactone ring to which are attached one or moredeoxy sugars. Other macrolide antibiotics include erythromycin andclarithromycin. Azithromycin and the other macrolide antibiotics arebacteriostatic agents which act by binding to the 50S ribosomal subunitof susceptible microorganisms, and thus interfering with microbialprotein synthesis.

Macrolide antibiotics of the erythromycin class, such as erythromycin A,are known to be unstable in an acidic environment and are inactivated bygastric acids. See, Goodman and Gilman's, The Pharmacological Basis ofTherapeutics 1137 (Joel G. Hardman et al., eds.) 9th ed. 1996; C.Vinckier et al., Int. J. Pharmaceutics, 55, 67-76 (1989); T. Cachet etal., Int. J. Pharmaceutics, 55, 59-65 (1989); E. F. Fiese and S. H.Steffen, J. Antimicrobial Chemother., 25 (suppl.A) 39-47 (1990).

Azithromycin is a semi-synthetic antibiotic which differs chemicallyfrom erythromycin in that a methyl-substituted nitrogen atom isincorporated into the lactone ring. The replacement of the keto group inthe lactone ring with the N-methyl group in the lactone ring improvesthe stability of azithromycin over erythromycin in an acidicenvironment.

U.S. Pat. Nos. 4,517,359 and 4,474,768 disclose processes for thepreparation of azithromycin and the use of azithromycin as anantibiotic. These patents are incorporated herein by reference.

Azithromycin is subject to degradation that may occur during manufactureand/or storage. For example, azithromycin is susceptible to degradationif exposed to elevated temperatures and/or air during manufacturingprocesses, processes that include formulation of the pharmaceuticaldosage form. One particular example of oxidative degradation is theoxidation of the exocyclic amine group of azithromycin. Thesusceptibility of azithromycin to degradation may lead to deviation ofthe drug product from regulatory purity requirements even prior to theproduct reaching the patient. In addition, once formulated, azithromycintends to degrade under normal storage conditions, which may result inthe presence of unacceptable levels of impurities at the time ofadministration.

Therefore, a continuing need exists to provide consistent dosages ofazithromycin by providing methods that delay or prevent the productionof degradation products by improving storage methods for azithromycin.Likewise, a continuing need exists to provide azithromycin compositionshaving a reduced tendency to degrade.

SUMMARY OF THE INVENTION

In some embodiments, the invention encompasses methods for packagingazithromycin which show improved stability of azithromycin upon storage.

For example, one embodiment encompasses methods for packagingazithromycin comprising storing azithromycin in a gas impermeablepackage made of at least one sheet of gas impermeable material, whereinafter storage azithromycin degradation products do not exceed 5%,preferably less than about 3% by weight of azithromycin. The gasimpermeable material is impermeable to oxidizing agents, preferably tooxygen. The gas impermeable package may be selected from any materialknown in the art. The sheet may be a laminated sheet preferably analuminum laminate package. The package may be comprised of a bag or apouch.

Another embodiment of the invention encompasses methods for storingazithromycin comprising storing azithromycin in a gas impermeablepackage comprising at least one layer, wherein the intimate layer isprepared from a gas impermeable material and is capable of being sealed.The gas impermeable material may be selected from any material known inthe art. The gas impermeable material is preferably an aluminumlaminate. After the storage azithromycin degradation products do notexceed 5%, preferably less than about 3% by weight of the azithromycin.In another embodiment, the azithromycin storage conditions include atleast one of a temperature of about 25° C. to about 55° C.; 60% relativehumidity; or a time of at least one month.

Another embodiment of the invention encompasses methods for packagingazithromycin comprising storing a unit dosage of azithromycin in a gasimpermeable package. The gas impermeable package may be selected fromany material known in the art. The gas impermeable package is preferablyan aluminum laminate package.

Another embodiment of the invention encompasses methods for packagingazithromycin wherein less than about 5% of azithromycin monohydrate istransformed to the dihydrate form on storage for one year.

The degradation products may be identified by HPLC relative retentiontimes of about 0.26, 0.34, 0.37, and 0.80.

In another embodiment, the invention is directed to stabilizedazithromycin compositions. A stabilized azithromycin compositionpreferably includes an intimate admixture of azithromycin and astabilizing-effective amount of an antioxidant. Coprecipitation andco-milling of azithromycin and an antioxidant are particularly preferredmethods of achieving an intimate admixture.

Another embodiment of the invention is directed to, a method forpreparing a stabilized azithromycin composition. The method comprisesdissolving azithromycin and a stabilizing-effective amount of anantioxidant in a solvent and co-precipitating the azithromycin andantioxidant, and, recovering a stabilized azithromycin composition.

Stabilized azithromycin compositions can also be prepared by dissolvingazithromycin and a stabilizing-effective amount of an antioxidant in afirst solvent to form a mixture; drying the mixture; redissolving themixture in a second solvent; co-precipitating azithromycin and theantioxidant and recovering a stabilized azithromycin composition.

Yet another method for making a stabilized azithromycin composition inaccordance with the present invention includes co-milling azithromycinand a stabilizing-effective amount of an antioxidant. In thisembodiment, co-milling may be achieved by, for example, grinding theazithromycin and antioxidant together by conventional means such asusing a mortar and pestle or co-micronization processes as are generallyknown in the art.

Once a stabilized azithromycin composition is prepared in accordancewith the present invention, it is preferably formulated intopharmaceutical formulations such as conventional dosage forms, includingtablets, capsules (e.g., hard and soft gelatin capsules), suspensions,sachets, dragees, suppositories, etc. Tablets are preferred dosageforms. Tablets may be made with the stabilized azithromycin compositionsand optional excipients by processes including, e.g., wet granulation,dry granulation such as slugging or compaction, or direct compression,followed by shaping into tablets.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the X-ray powder diffraction pattern for azithromycinForm A.

FIG. 2 illustrates the X-ray powder diffraction pattern for thedihydrate.

FIG. 3 is an HPLC chromatogram depicting elution profiles ofazithromycin standards.

FIG. 4 is an HPLC chormoatogram depicting typical elution profiles ofazithromycin impurities.

FIG. 5.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise indicated, the term “azithromycin” includes salts,solvates, hydrates thereof, and physiologically functional derivativesthereof, e.g. propanol solvate, ethanol solvate, monohydrate and othercrystalline and polymorph forms.

The term “Form A” refers to a crystalline form of azithromycin having anX-ray powder diffraction with peaks at 6.3, 8.0, 10.0, 11.4, 11.6, 12.0,12.6, 14.0, 14.5, 14.7, 15.0, 15.4, 15.9, 17.3, 18.7, 19.1, 20.0, 20.3,and 21.2 degrees two-theta. The peaks of Form A are listed in FIG. 1.

The term “dihydrate azithromycin” refers to a crystalline form ofazithromycin having an X-ray powder diffraction with peaks at 9.3, 12.1,13.0, 16.4, and 18.7 degrees two-theta. The peaks of the dihydrate arelisted in FIG. 2.

As used herein, the term “AZT” refers to azithromycin. As used herein,the term “DMAZT” refers to azithromycin A (USP), desmethyl azithromycin.DMZAT is an intermediate used in the synthesis of azithromycin. The term“TAZT” refers to tosyl azithromycin. The term “BH” refers to butylatedhydroxyanisole. The term “BHT” refers to butylated hydroxytoluene. Theterm “PG” refers to propyl gallate. The term “PVP” refers topolyvinylpyrrolidone. The term “SLS” refers to sodium lauryl sulfate.The term “LOD” refers to loss on dry. The terms “API” and “Apr” refersto active pharmaceutical ingredient. The term “intimate layer” refers tothe layer of gas impermeable packaging which contacts the storedmaterial.

As used herein, the term “gas impermeable” refers to a property of amaterial wherein the passage of gases through the material is delayed orprohibited. As used with packaging, “gas impermeable” refers to thepackaging of products having improved barrier characteristics betterthan those of low density polyethylene (LDPE) having been manufacturedby coextrusion, lamination, metallization, or coating.

As used herein, the term “unit dosage form” refers to the amount ofazithromycin, or a derivative thereof, which is effective to produce atherapeutic effect in a subject.

As used herein, the term “lamination” refers to a situation when two ormore individuals films are bonded together with special adhesives andrun through rolling, heated cylinders to produce a composite filmstructure.

The term “stabilizing-effective amount,” used in reference to the amountof antioxidant in the stabilized azithromycin composition, means (1) anamount such that no more than about 3.8%, preferably no more than about1.2%, and, most preferably, no more than about 0.86% by weight ofazithromycin in the stabilized azithromycin composition is degraded uponexposure to 55° C. for seven days or, (2) an amount such that no morethan about 1.25%, preferably no more than about 0.8%, and, mostpreferably, no more than about 0.35% by weight of azithromycin in thestabilized azithromycin composition is degraded upon exposure to 50° C.for 20 hours.

DESCRIPTION OF THE INVENTION

Azithromycin is unstable and prone to produce degradation products uponmanufacture and/or storage and/or when exposed to temperatures aboveabout 25° C. Not to be bound by theory, it is believed that onedegradation pathway is the oxidation of azithromycin in the presence ofoxidizing agents, such as oxygen. The degradation products may beidentified by HPLC relative retention times of about 0.26, 0.34, 0.37,and 0.80.

Thus, in one aspect, the invention encompasses methods of storingazithromycin and containers for storing azithromycin comprising at leastone gas impermeable material wherein the containers diminish or protectazithromycin from either: a) degradation, in particular degradation byoxidation, or b) changing of azithromycin solvate composition (water orsolvent or a combination thereof as compared to the composition beforeAZT is packaged).

The advantage of using at least one gas impermeable container to protectazithromycin from oxidation is the increase in azithromycin shelf life.

Also, the invention encompasses containers for storing azithromycincomprising at least one gas impermeable material effective to protectazithromycin from degradation, especially at elevated temperatures.

One embodiment of the invention encompasses containers for storingazithromycin comprising a container having at least one gas impermeablematerial and capable of being sealed. Generally, the container mayinclude bottles, jar, pouches, envelopes, bags, and the like.Preferably, the container is in the form of a pouch or bag and comprisesat least one gas impermeable material in the form of a sheet. The gasimpermeable package may be selected from any material known in the artto be gas impermeable. Preferably, the material is oxygen and/or airimpermeable. Preferably, the material is in the form of at least onelaminate aluminum containing polymer. More preferably, the material isin the form of laminate aluminum containing polymer. An example of thepolymer is polyethylene. The sheet may contact itself to form anenvelope or a bag or may contact a second sheet of gas impermeablematerial to form a cavity wherein the azithromycin is placed.

There may be a better stabilizing effect of proposed double aluminumlaminate instead of polyethylene in aluminum laminate.

Another embodiment of the invention encompasses methods for storingazithromycin comprising placing azithromycin in a container comprisingat least one gas impermeable layer having an exterior and an intimatelayer, wherein the intimate layer is prepared from a gas impermeablematerial and is capable of being sealed. The azithromycin may be in theform of a unit dosage of azithromycin. The unit dosage form may be a 250mg, 500 mg, or 600 mg unit.

Another embodiment of the invention encompasses methods for packagingazithromycin, wherein the packaging delays or prevents azithromycin fromdegradation caused by water, oxygen, or both. As used herein, the term“delay or prevents degradation” as applied to azithromycin refers to theformation of no more than 5% by weight of azithromycin degradationproducts, preferably, no more than 3% by weight of degradation products.In another embodiment, the azithromycin storage conditions include atleast one of a temperature of about 25° C. to about 55° C.; 60% relativehumidity; or a time of at least one month. Alternatively, the packagingallows for less than about 5% of azithromycin monohydrate to transformto azithromycin dihydrate upon storage for one year. In anotherembodiment, the azithromycin storage conditions include at least one ofa temperature of about 25° C. to about 55° C.; wherein at 55° C. withuncontrolled humidity the azithromycin monohydrate is stable for atleast one month, preferable for at least 3 months, and wherein at 25° C.with 60% relative humidity, the azithromycin monohydrate is stable forat least one month, preferable at least 3 months and more preferably forat least one year.

The regular packaging material, which is used for stability studies, ispolyethylene of low density wrapped into aluminum laminate. Thepolyethylene of low density is penetrable for gases.

The stability of azithromycin is substantially increased when thematerial is packed directly in aluminum laminate bags. Use of thispackaging material enables one to store safely the azithromycin atnormal temperatures.

It has also been found that the addition of antioxidants to azithromycinprotects azithromycin from degradation at elevated temperatures, whichmay be due to oxidation and/or other means.

Thus, some of embodiments of the present invention are directed to astabilized azithromycin composition. In several embodiments, theazithromycin used is azithromycin ethanolate monohydrate. Azithromycinethanolate monohydrate is a stable azithromycin compound disclosed inU.S. Pat. No. 6,365,574, which is incorporated herein by reference.

In one embodiment, the stabilized azithromycin composition comprisesazithromycin and an stabilizing-effective amount of an antioxidant. Asused herein, “antioxidant” refers to a substance known to inhibitoxidation. Among preferred antioxidants suitable for use in accordancewith the present invention are included ascorbic acid, sodium ascorbate,calcium ascorbate, ascorbic palmitate, butylated hydroxyanisole,butylated hydroxytoluene, 2,4,5-trihydroxybutyrophenone,4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac,propyl gallate, thiodipropionic acid, dilauryl thiodipropionate,tert-butylhydroquinone and tocopherols such as vitamin E, and the like,including pharmaceutically acceptable salts and esters of thesecompounds. Preferably, the antioxidant is a food grade antioxidant,however any antioxidant which is generally recognized aspharmaceutically acceptable may be used.

More preferably, the antioxidant is butylated hydroxyanisole, butylatedhydroxytoluene, propyl gallate, ascorbic acid, pharmaceuticallyacceptable salts or esters thereof, or mixtures thereof. Mostpreferably, the antioxidant is butylated hydroxytoluene or sodiumascorbate.

Preferably, the antioxidant is present in the stabilized azithromycincompositions in an effective amount to retard or prevent degradation ofazithromycin, thereby stabilizing the azithromycin. Preferably, theamount of antioxidant is in the range of about 0.01-10% by weightazithromycin. More preferably, the amount of antioxidant is in the rangeof about 0.1-5% by weight azithromycin. In preferred embodiments, (1)the amount of antioxidant used is such that no more than about 3.8%,preferably no more than about 1.2%, and, most preferably, no more thanabout 0.86% by weight of azithromycin in the stabilized azithromycincomposition is degraded upon exposure to 55° C. for seven days, or (2)the amount of antioxidant used is such that no more than about 1.25%,preferably no more than about 0.8%, and, most preferably, no more thanabout 0.35% by weight of azithromycin in the stabilized azithromycincomposition is degraded upon exposure to 50° C. for 20 hours.

In another aspect, the present invention is directed to a method formanufacturing a stabilized azithromycin composition.

In one embodiment, the stabilized azithromycin composition is made bythe addition of an antioxidant to a solution of azithromycin beforecrystallizing the azithromycin from the solution. Upon crystallization,a co-precipitate of azithromycin and antioxidant is formed and recoveredfrom the solution. The co-precipitate comprises azithromycin andantioxidant in intimate admixture. The stabilized composition ofazithromycin may then be formulated into suitable dosage forms withconventional excipients.

In another embodiment, the stabilized azithromycin composition is madeby the addition of an antioxidant to an azithromycin solution at theonset of crystallization of azithromycin from the solution. Aco-precipitate of azithromycin and antioxidant is formed and recoveredfrom the solution. The co-precipitate comprises azithromycin andantioxidant in intimate admixture. The stabilized composition ofazithromycin may then be formulated into suitable dosage forms withconventional excipients.

In yet another embodiment, a stabilized azithromycin composition is madeby addition of an antioxidant to an azithromycin solution and thepartial or total evaporation of the solvent. Preferably, this embodimentcomprises the steps of: 1) dissolving azithromycin and an antioxidant ina first solvent; 2) evaporating the first solvent to form a dry residue;3) redissolving the dry residue in a second (not necessarily different)solvent; 4) crystallizing azithromycin and 5) adding additionalantioxidant at the onset of crystallization. A co-precipitate ofazithromycin and antioxidant is formed and recovered from the solution.The co-precipitate comprise azithromycin and antioxidant in intimateadmixture. The stabilized composition of azithromycin may then beformulated into suitable dosage forms with conventional excipients.

The preferred solvent in the disclosed methods is an alcohol. Morepreferably, the solvent is a lower straight or branched-chain alkanolsuch as ethanol, propanol, isopropanol, etc.

In still another embodiment, a stabilized azithromcyin composition ismade by co-milling azithromycin and antioxidant to form an intimateadmixture. Co-milling may be done by grinding the azithromycin andantioxidant using conventional methods such as with a mortar and pestleor by co-micronizing the azithromycin and antioxidant.

In another aspect, the present invention is directed to pharmaceuticalformulations comprising a stabilized azithromycin composition asdescribed herein and methods for making such pharmaceuticalformulations. The pharmaceutical formulations typically contain, inaddition to the stabilized azithromycin composition, one or morepharmaceutically acceptable excipients, such as binders, fillers,disintegrants, carriers, lubricants, glidants, flavorants, colorants,buffers, thickening agents, etc. Some excipients can serve multiplefunctions, for example as both binder and disintegrant.

The pharmaceutical formulations comprising a stabilized azithromycincomposition include dosage forms such as tablets, granulates, dragees,hard or soft capsules, powders, solutions, emulsions, suspensions, orthe like. Tablets are particularly preferred dosage forms of thepharmaceutical formulations in accordance with the present invention.Among the methods for forming preferred tablet dosage forms areincluded, e.g., wet granulation, dry granulation, e.g., compaction andslugging, and direct compression.

Examples of tablet disintegrants useful in accordance with the presentinvention are starch, pregelatinized starch, sodium starch glycolate,sodium carboxymethylcellulose, cross inked sodium carboxymethylcellulose(sodium croscarmellose; crosslinked starch available under theregistered trademark Ac-Di-Sol from FMC Corp., Philadelphia, Pa.), clays(e.g. magnesium aluminum silicate), microcrystalline cellulose (of thetype available under the registered trademark Avicel from FMC Corp. orthe registered trademark Emcocel from Mendell Corp., Carmel, N.Y.),alginates, gums, surfactants, effervescent mixtures, hydrous aluminumsilicate, cross-linked polyvinylpyrrolidone (available commerciallyunder the registered trademark PVP-XL from International SpecialtyProducts, Inc.), and others as known in the art.

Among preferred disintegrants are sodium croscarmellose (Ac-Di-Sol),sodium starch glycolate (available commercially under the registeredtrademarks Primojel from Avebe (Union, N.J.) or Generichem, (LittleFalls, N.J.), pregelatinized starch and Explotab from Mendell Corp.),microcrystalline cellulose (Avicel), and cross-linkedpolyvinylpyrrolidone (PVP-XL).

Examples of binders include, e.g., acacia, cellulose derivatives (suchas methylcellulose and carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol,polymethacrylates, polyvinylpyrrolidone, starch paste, sucrose,sorbitol, pregelatinized starch, gum tragacanth, alginic acids and saltsthereof such as sodium alginate, magnesium aluminum silicate,polyethylene glycol, guar gum, bentonites, and the like.

Flavors incorporated in the composition may be chosen from syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants leaves, flowers, fruits, and so forth and combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils,clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil,oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil. Alsouseful as flavors are vanilla, citrus oil, including lemon, orange,grape, lime and grapefruit, and fruit essences, including apple, banana,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot,and so forth. The amount of flavoring may depend on a number of factorsincluding the organoleptic effect desired. Generally the flavoring willbe present in an amount of from 0.5 to about 3.0 percent by weight basedon the total tablet weight, when a flavor is used.

A variety of materials may be used as fillers or diluents. Examples arespray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol,starch (e.g. starch 1500), cellulose (e.g. microcrystalline cellulose;Avicel), dihydrated or anhydrous dibasic calcium phosphate (availablecommercially under the registered trademark Emcompress from Mendell orA-Tab and Di-Tab from Rhone-Poulenc, Inc., Monmouth Junction, N.J.),calcium carbonate, calcium sulfate, and others as known in the art. Apreferred filler in accordance with the present invention is dibasiccalcium phosphate dihydrate or anhydrous.

Lubricants can also be employed herein in the manufacture of certaindosage forms, and will usually be employed when producing tablets.Examples of lubricants are magnesium stearate, talc, stearic acid,glycerylbehenate, polyethylene glycol, ethylene oxide polymers (forexample, available under the registered trademark Carbowax from UnionCarbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium laurylsulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidalsilica, and others as known in the art. Preferred lubricants aremagnesium stearate, and mixtures of magnesium stearate with sodiumlauryl sulfate. Lubricants generally comprise 0.5 to 7.0% of the totaltablet weight.

Other excipients such as glidants and coloring agents may also be addedto azithromycin tablets. Coloring agents may include titanium dioxideand/or dyes suitable for food such as those known as F. D. & C, dyes andnatural coloring agents such as grape skin extract, beet red powder,beta carotene, annato, carmine, turmeric, paprika, and so forth. Acoloring agent is an optional ingredient in the compositions of thisinvention, but when used will generally be present in an amount up toabout 3.5 percent based on the total tablet weight.

As known in the art, tablet blends may be dry-granulated or wetgranulated before tableting. Alternatively, tablet blends may bedirectly compressed. The choice of processing approach depends upon theproperties of the drug and chosen excipients, for example particle size,blending compatibility, density and flowability. For azithromycintablets, granulation is preferred, with wet granulation being mostpreferred. The stabilized azithromycin composition may bewet-granulated, and then other excipients may be added extragranularly.Alternatively, the stabilized azithromycin composition and one or moreexcipients may be wet-granulated. Dry granulation, such as compactionand/or slugging with or without an intragranular excipient may also beused to make the tablets, followed by tabletting with or withoutextragranular excipients. In addition, tablets may also be coated, witha coating that exhibits little or no effect on or interference withtablet dissolution, to assure ease of swallowing or to provide anelegant appearance.

Tablets may be film-coated to provide ease of swallowing and an elegantappearance. Many polymeric film-coating materials are known in the art,including, e.g., hydroxypropylmethylcellulose (HPMC). HPMC may beobtained commercially, for example from Colorcon Corp., in coatingformulations containing excipients which serve as coating aids, underthe registered trademark Opadry. Opadry formulations may containlactose, polydextrose, triacetin, polyethyleneglycol, polysorbate 80,titanium dioxide, and one or more dyes or lakes. Other suitablefilm-forming polymers also may be used herein, including,hydroxypropylcellulose, and acrylate-methacrylate copolymers.

Conventional tableting processes are employed, e.g., by forming a tabletfrom a desired blend or mixture of ingredients into the appropriateshape using a conventional tablet press. Tablet formulation andconventional processing techniques have been widely described, forExample in Pharmaceutical Dosage Forms: Tablets; Edited By Lieberman,Lachman, and Schwartz; Published by Marcel Dekker, Inc., 2d Edition,Copyright 1989, the text of which is herein incorporated by reference.

The azithromycin dosage forms of this invention also include powders tomake oral suspensions, and also the oral suspensions themselves.Generally the powder is a non-caking, free flowing powder which is solddirect to pharmacies or other retail outlets and then made up into theactual suspension by a pharmacist. The oral suspension is thus theactual dosage form ingested by patients.

Azithromycin suspensions may contain, e.g., in addition to a stabilizedazithromycin composition, one or more thickening agents, a buffer orpH-altering agent. Dispersing agents may also be used to facilitateformation of a suspension.

Suitable thickening agents function as suspending agents and include,for example, hydrocolloid gums known for such purpose, examples of whichinclude xanthan gum, guar gum, locust bean gum, gum tragacanth, and thelike. Alternatively, synthetic suspending agents may be used such assodium carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose and the like. Dispersing agents include colloidalsilicon dioxide, available from Cabot Corporation, Boston, Mass. underthe trade designation Cab-O-Sil.

A powder used to make a suspension may also contain conventionaloptional ingredients such as (1) wetting agents such as sorbitanmonolaurate, polysorbate 80, and sodium lauryl sulfate; (2) anti-foamingagents and (3) sweeteners and fillers such as glucose. The powder mayalso contain a buffer to maintain a high pH upon reconstitution, asdiscussed above. Suitable buffers and pH-altering agents includetribasic sodium phosphate, anhydrous sodium carbonate, glycine, and thelike. Suitable preservatives are well known, for example sodium benzoateand the like.

A stabilized azithromycin composition in accordance with the presentinvention may be formulated in a unit dose packet dosage form or sachet.Such a packet will typically contains a blend of azithromycin andexcipients which is thus reconstituted. In addition to a stabilizedazithromycin composition in accordance with the present invention, thepacket may contain, for example, a dispersing agent which makes thesachet powder free flowing, for example colloidal silicon dioxide suchas Cab-O-Sil from Cabot. The dispersing agent may also serve as aglidant. The formulation may also optionally contain ingredientsincluding (1) a filler or sweetener (e.g. glucose); (2) a buffer (e.g.sodium phosphate); (3) a wetting agent such as a surfactant, for examplesodium lauryl sulfate, and (4) flavors such as any of those enumeratedherein, and the like. The powder in the packet flows freely anddisperses quickly, essentially immediately upon stirring whenreconstituted.

EXAMPLES

Although the following examples illustrate the practice of the presentinvention in some of its embodiments, the examples should not beconstrued as limiting the scope of the invention. Other embodiments willbe apparent to one skilled in the art from consideration of thespecification and examples.

Example 1

Several azithromycin samples were analyzed using HPLC to determine thelevel of impurities within each sample. The analytical conditions of theHPLC were column of 150×4.6 mm; packing material of Kromasil KR100-5C18, 5Φ; and an eluent of 40% 0.05 M K₂HPO₄ adjusted to a pH of 8.2and 60% acetonitrile. The flow rate was 0.9 ml/min; the detector set at210 nm; and column temperature of 30° C. The samples were injected intothe HPLC and run for over 35 min. The impurities were determined bytheir relative retention times (RRT) as compared to azithromycin andwere reported as a weight percent (versus azithromycin) of the totalcomposition. Additional impurities found in the samples were reportedunder “other RRT” as a weight percent of the azithromycin content. Theresults of the analytical tests is summarized in Table A. Table Ademonstrates a finding of the main azithromycin degradation productswhere azithromycin batches have been stored under uncontrolledtemperature conditions (25° C. and higher) in regular packages (intimatepackage is LDPE and exterior is aluminum laminate). The lowest row ofthe table sums up each impurity content for all batches. The raw datareveals that the main degradants of azithromycin upon storage are RRT0.26, 0.34, 0.37, and 0.80. RRT (%) Other Total AZT Batch 0.16 0.18 0.230.26 0.34 0.37 0.40 0.49 0.60 0.80 0.88 RRT % % Batch 1 ND <0.1 ND 0.130.45 0.14 ND ND ND 0.25 ND 0.45 1.7 Batch 2 ND <0.1 ND ND 0.32 <0.1 NDND ND 0.24 ND 0.49 1.3 Batch 3 0.15 ND ND 0.16 0.64 0.32 ND ND ND <0.1ND 0.64 1.5 Batch 4 ND ND ND <0.1 <0.1 <0.1 ND <0.1 ND <0.1 ND 0.00 0.0Batch 5 ND ND ND <0.1 <0.1 <0.1 ND <0.1 ND 0.11 ND 0.11 0.2 Batch 6 ND<0.1 ND <0.1 ND <0.1 <0.1 <0.1 ND ND ND 0.00 0.0 Batch 7 ND <0.1 ND <0.1<0.1 <0.1 ND ND ND ND ND 0.16 0.2 Batch 7 ND <0.1 ND 0.41 0.37 0.23 0.22ND ND 0.20 ND 0.41 1.4 Batch 8 ND <0.1 ND 0.14 0.16 <0.1 ND ND ND ND ND0.16 0.4 Batch 8 ND <0.1 ND 0.28 0.28 0.19 0.21 ND ND 0.14 ND 0.28 1.2Batch 9 ND ND ND ND <0.1 <0.1 ND ND ND ND ND 0.00 0.0 Batch 9 ND ND ND0.29 0.40 0.17 ND <0.1 ND 0.12 ND 0.40 1.2 Batch 10 ND ND <0.1 ND 0.13<0.1 ND ND ND <0.1 ND 0.13 0.2 Batch 10 ND ND ND <0.1 0.18 0.11 ND 0.10ND <0.1 ND 0.18 0.5 Batch 11 ND ND ND <0.1 0.13 <0.1 ND <0.1 ND <0.1 ND0.16 0.4 Batch 12 <0.1 ND <0.1 0.18 0.23 <0.1 <0.1 ND ND <0.1 ND 0.230.5 Sum of 0.15 0.00 0.00 1.59 3.29 1.16 0.43 0.10 0.00 1.06 0.00impurities

Example 2 Storage Testing

Three samples of azithromycin were separately packaged in a standardpolyethylene bag, and then the polyethylene bags containing azithromycinwere separately packaged into aluminum bags with silica gel. The storedazithromycin was submitted to stability programs either long term oraccelerated to determine the effect upon azithromycin stability and theproduction of degradation products. The longer term stability programcomprised submitting the sample to a temperature of about 25° C.±2° C.at a relative humidity of 60%±5%. The accelerated program comprisedsubmitting the sample to a temperature of about 40° C.±2° C. at arelative humidity of 75%+5%. The samples were analyzed at regularintervals to determine the impurity profiles as assayed by HPLC usingthe technique described in Example 1. The water content was determinedby Karl Fischer methodology; and the ethanol content was determined bygas chromatography. The results of these tests are summarized in TableB, where “Any %” means any kind of impurity that gives the highestcontent in azithromycin. TABLE B Azithromycin Stability in polyethylenebag Impurities AZT Time Temp. Any Total % % Batch (months) (° C.) % %Water Ethanol Batch 0 0.12 0.33 2.99 2.2 No. 4 3^(a) 25° C. 0.55 2.142.97 2.2 1^(b) 40° C. 0.45 1.93 3.13 2.1 2^(b) 0.65 3.10 2.65 1.8 3^(b)0.77 3.71 2.95 1.8 Batch 0 0.12 0.22 3.83 1.9 No. 5 3^(a) 25° C. 0.492.17 2.93 1.8 1^(b) 40° C. 0.43 1.77 3.22 1.8 2^(b) 0.72 2.78 2.86 1.63^(b) 1.11 5.07 3.27 1.5 Batch 0 <0.1% <0.1% 3.78 2.0 No. 6 3^(a) 25° C.0.32 1.40 2.75 2.0 1^(b) 40° C. 0.44 1.71 3.21 1.9 2^(b) 0.62 2.08 2.801.9 3^(b) 0.81 3.94 3.12 1.7^(a)Long term program.^(b)Accelerated program.

Evaluation of results shown in Table B demonstrated that moredegradation products were produced at higher temperatures, i.e. 40° C.,as compared to either the starting material or at lower temperatures,i.e. 25° C. Table C contains a detailed presentation of the impurityprofile for the tested batches wherein the impurities were reported asby RRT and weight percentage of the total composition. TABLE C ExtendedAnalytical Profile for Azithromycin AZT Time Temp Impurities RRT (%)Batch (months) ° C. 0.26 0.35 0.38 0.40 0.82 Batch 0 <0.1 0.12 <0.1 <0.1No. 4 3^(a) 25 0.40 0.43 0.29 0.21 0.34 1^(b) 40 0.45 0.42 0.28 0.220.31 2^(b) 0.65 0.61 0.50 0.22 0.46 3^(b) 0.72 0.77 0.50 0.37 0.61 3^(b)55 0.78 0.91 0.61 0.34 0.73 Batch 0 <0.1 <0.1 <0.1 <0.1 0.12 No. 5 3^(a)25 0.49 0.46 0.44 0.15 0.18 1^(b) 40 0.39 0.43 0.23 0.25 0.25 2^(b) 0.590.72 0.37 0.19 0.35 3^(b) 1.41 0.76 0.72 0.19 0.52 3^(b) 55 1.27 1.191.22 0.06 0.91 Batch 0 <0.1 <0.1 <0.1 <0.1 <0.1 No. 6 3^(a) 25 0.31 0.320.3 0.1 0.12 1^(b) 40 0.44 0.40 0.26 0.25 <0.1 2^(b) 0.49 0.62 0.27 0.160.20 3^(b) 0.74 0.71 0.67 0.19 0.47 3^(b) 55 0.92 0.87 0.92 0.06 0.65^(a)Long term program.^(b)Accelerated program.

Example 3 Azithromycin Stability as a Function of Storage Temperature

Samples of azithromycin were placed in storage bags and each batchsample was analyzed after storage at a variety of temperatures using theanalytical techniques as described in Example 1. Each batch was packagedin a polyethylene bag and subsequently, each bag was packaged in analuminum bag with silica gel. Table D summarizes the effects of storagetemperature on the production of azithromycin degradation products. Theresults demonstrate that storing azithromycin at low temperatures (+5°C.) leads to inhibition of the production of degradation products. TABLED Azithromycin Stability as a Function of Storage Temperature AZT TimeRRT (%) Other Total Batch (months) T° C. 0.26 0.34 0.37 0.80 RRT % %Batch 0 <0.1 0.07 0.03 <0.1 <0.1 0.1 No. 4 3 2-8 0.07 0.12 0.06 0.060.12 0.3 3 25 0.36 0.41 0.26 0.32 0.41 1.5 Batch 0 <0.1 0.07 0.03 <0.1<0.1 0.1 No. 5 3 2-8 0.10 0.15 0.07 0.08 0.15 0.4 3 25 0.44 0.62 0.390.43 0.62 1.9 Batch 0 <0.1 0.13 0.07 0.04 0.13 0.2 No. 6 3 2-8 0.07 0.170.11 0.03 0.17 0.4 3 25 0.39 0.57 0.32 0.34 0.57 1.8

Example 4 Azithromycin Stability as a Function of Layered StorageContainer

Five different samples of azithromycin were stored in a variety ofpackages to determine the amount of degradation products after aparticular time and temperature. Using HPLC analytical methodology asdescribed in Example 1, the presence and amount of degradation productsfor each package were determined. Each sample was packaged directly intoan aluminum laminate, or packaged in an inner polyethylene (PE) bag andexterior aluminum laminate bag. Each sample was stored at an elevatedtemperature for 6-7 days. The results demonstrate that fewerazithromycin degradation products were found in the aluminum laminatebags as compared to the polyethylene/aluminum laminate double bag. TableE summarizes the effect of different packaging on the stability ofazithromycin. TABLE E Azithromycin Stability as a Function of Time RRT(%) AZT Time Other Batch Package (days) T° C. 0.25 0.33 0.36 0.78 0.80RRT % Batch 0 <0.1 0.12 <0.1 <0.1 <0.1 0.12 No. 4 direct in Al laminate6 55 0.17 0.14 0.07 0.11 <0.1 0.17 PE bag in Al laminate 6 55 0.49 0.480.26 0.35 <0.1 0.49 Batch 0 0.09 0.08 0.03 <0.1 0.06 0.10 No. 5 directin Al laminate 6 55 0.13 0.10 0.03 0.08 0.07 0.13 PE bag in Al laminate6 55 0.36 0.36 0.15 0.2 0.06 0.36 Batch 0 0.05 0.05 0.03 <0.1 <0.1 <0.1No. 13 direct in Al laminate 6 55 0.14 0.12 0.05 0.05 <0.1 0.14 PE bagin Al laminate 6 55 0.42 0.44 0.19 0.27 <0.1 0.44 Batch 0 0.37 0.38 0.19<0.1 0.22 0.38 No. 7 direct in Al laminate 7 55 0.37 0.39 0.14 <0.1 0.220.39 PE bag in Al laminate 7 55 0.49 0.51 0.26 <0.1 0.28 0.51 Batch 00.08 0.18 0.08 <0.1 <0.1 0.18 No. 10 direct in Al laminate 7 55 0.120.25 0.10 <0.1 0.06 0.25 PE bag in Al laminate 7 55 0.24 0.41 0.18 <0.10.15 0.41

Example 5 Double Aluminum Laminate Package Studies

Different batches of azithromycin were packaged in double aluminumlaminate bags under a variety of conditions. The storage conditionsincluded long term (2° C. to 8° C.); humid long term (25° C.±2° C. at60%±5% relative humidity); humid accelerated (25° C.±2° C. at 60%±5%relative humidity); and high humidity accelerated (40° C. at 70%±5%relative humidity). After a predetermined amount of time, each samplewas analyzed according to the analytical technique described inExample 1. Table F summarizes the test data. The decomposition ofazithromycin in a double layer of aluminum laminate packaging wassignificantly inhibited. Even at a temperature of 40° C., the impurityincrease was very moderate and close to the results at 25° C. TABLE FAzithromycin Stability in Double Aluminum Bags. Impurities AZT Time RRT(%) Other % % Batch (months) 0.26 0.34 0.37 0.78 RRT % Total % WaterEtOH Batch 0 0.29 0.40 0.17 0.12 0.40 1.30 3.22 2.1 No. 10 3^(a) 0.240.32 0.16 0.15 0.32 0.98 3.40 2.1 3^(b) 0.30 0.39 0.18 0.21 0.39 1.293.69 2.1 1^(c) 0.29 0.40 0.20 0.22 0.40 1.22 2.90 2.2 2^(c) 0.33 0.330.25 0.20 0.33 1.31 3.31 2.1 3^(c) 0.30 0.39 0.18 0.21 0.39 1.29 3.692.1 1^(d) 0.34 0.49 0.22 0.19 0.49 1.35 3.17 2.2 2^(d) 0.40 0.37 0.350.24 0.40 1.57 3.11 2.2 3^(d) 0.38 0.46 0.25 0.28 0.46 1.47 3.46 2.2Batch 0 <0.10 0.18 0.11 <0.10 0.18 0.53 3.66 2.2 No. 11 3^(a) <0.10 0.15<0.10 <0.10 0.15 0.26 3.90 2.1 3^(b) <0.10 0.19 0.12 <0.10 0.19 0.543.75 2.1 1^(c) <0.10 0.20 <0.10 <0.10 0.20 0.37 3.69 2.1 2^(c) <0.100.16 0.12 <0.03 0.16 0.41 3.77 2.1 3^(c) <0.10 0.19 0.12 <0.10 0.19 0.543.75 2.1 1^(d) 0.12 0.24 0.12 <0.10 0.24 0.75 3.65 2.1 2^(d) 0.15 0.180.18 <0.10 0.18 0.65 3.47 2.2 3^(d) 0.21 0.31 0.15 0.11 0.31 0.90 3.842.1 Batch 0 <0.03 0.13 <0.10 <0.03 0.16 0.42 3.67 2.2 No. 12 3^(a) <0.10<0.10 <0.10 <0.10 0.14 0.25 3.69 2.1 3^(b) <0.10 0.17 <0.10 <0.10 0.160.42 3.64 2.2 1^(c) <0.10 0.17 <0.10 <0.10 0.17 0.30 3.51 2.1 2^(c)<0.10 0.12 0.11 <0.10 0.13 0.57 3.64 2.1 3^(c) <0.10 0.17 <0.10 <0.100.17 0.39 3.64 2.2 1^(d) 0.13 0.26 <0.10 <0.10 0.26 0.52 3.63 2.1 2^(d)0.15 0.17 0.15 <0.10 0.17 0.60 3.44 2.2 3^(d) 0.13 0.22 <0.10 <0.03 0.220.60 3.73 2.2^(a)Long term.^(b)Humid long term.^(c)Humid accelerated.^(d)High humidity accelerated.

Example 6 Year Long Azithromycin Study

Samples of azithromycin Form A were separately packaged intopolyethylene/aluminum laminate bags, and each polyethylene/aluminumlaminate bag was packaged into a second polyethylene/aluminum laminatebag. Each bag was subjected to a stability program (a) 25° C.±2° C. at60% relative humidity or (b) 40° C.±2° C. at 75% relative humidity.After one year, each sample was analyzed as described in Example 1 todetermine the presence and amount of degradation products. The impuritylevel for each sample was determined to be not more than 0.5%. Thus,each tested batch demonstrated the stability of azithromycin of greaterthan 1 year. Storage Lot No. Conditions Interval RRT = 0.26 RRT = 0.34RRT = 0.37 RRT = 0.78 Total Lot 1 25° C./60% RH 0 MT <0.10 0.18 0.11<0.10 0.53 25° C./60% RH 1 MT <0.10 0.20 <0.10 <0.10 0.37 25° C./60% RH2 MT <0.10 0.16 <0.03 <0.03 0.41 25° C./60% RH 3 MT <0.10 0.19 <0.10<0.10 0.54 25° C./60% RH 6 MT 0.11 0.19 <0.10 <0.10 0.53 25° C./60% RH 9MT 0.13 0.19 <0.10 <0.10 0.60 25° C./60% RH 12 MT  0.15 <0.10 <0.10<0.10 0.60 25° C./60% RH 18 MT  0.17 0.19 <0.10 <0.10 0.91 Lot 1 40°C./75% RH 0 MT <0.10 0.18 0.11 <0.10 0.53 40° C./75% RH 1 MT 0.12 0.240.12 <0.10 0.75 40° C./75% RH 2 MT 0.15 0.18 0.18 <0.10 0.65 40° C./75%RH 3 MT 0.21 0.31 0.15 0.11 0.90 40° C./75% RH 6 MT 0.34 0.34 0.22 0.121.30 Lot 2 25° C./60% RH 0 MT <0.03 0.13 <0.10 <0.03 0.42 25° C./60% RH1 MT <0.10 0.17 <0.10 <0.10 0.30 25° C./60% RH 2 MT <0.10 0.12 0.11<0.10 0.57 25° C./60% RH 3 MT <0.10 0.17 <0.10 <0.10 0.39 25° C./60% RH6 MT 0.1 0.15 0.10 <0.10 0.46 25° C./60% RH 9 MT 0.16 0.16 0.14 <0.100.70 25° C./60% RH 12 MT  0.18 0.25 0.16 0.11 1.00 25° C./60% RH 18 MT 0.15 0.26 <0.10 0.11 0.89 Lot 2 40° C./75% RH 0 MT <0.03 0.13 <0.10<0.03 0.42 40° C./75% RH 1 MT 0.13 0.26 <0.10 <0.10 0.52 40° C./75% RH 2MT 0.15 0.17 0.15 <0.10 0.60 40° C./75% RH 3 MT 0.13 0.22 <0.10 <0.030.60 40° C./75% RH 6 MT 0.16 <0.10 0.12 <0.10 0.56The typical peak of azithromycin dihydrate in Form A is 13.2 degreestwo-theta.

Example 7 Azithromycin Monohydrate Stability

A sample of azithromycin monohydrate is packaged into apolyethylene/aluminum laminate bag. The storage conditions include atemperature of about 25° C. and/or 60% relative humidity. After 3months, the X-ray diffraction pattern shows that less than about 5% ofazithromycin monohydrate is transformed to the dihydrate form.

General Disclosure with Respect to the Below Examples

The dibasic calcium phosphate dihydrate used was Emcompress®, which isavailable from Penwest Pharmaceuticals Co., Cedar Rapids, Iowa. Thesodium starch glycolate used was Explotabg, which is also available fromPenwest Pharmaceuticals. Sodium lauryl sulfate was used as received fromCognis (Henkel). The povidone used was povidone K-25 as received fromISP Pharmaceuticals. The colloidal silicon dioxide used was eitherCab-O-Sil®, available from Astro Chemicals Inc., Springfield, Mass., orAerosil 200®, available from Degussa. The dibasic calcium phosphate usedwas A-Tab, which is available from Rhodia (Rhone Poulenc). Thepregelatinized starch used was Starch 1500®, which is available fromColorcon. The croscarmellose sodium used was Ac-Di-Sol®, which isavailable from Farma International. The tablet coating used was Opadry®,which is available from Colorcon. The xanthan gum used is available fromKelco.

Quantitation Method Used in Accelerated Stability Studies

The quantity of impurities present before and after oxidative stresswere quantified by high performance liquid chromatography, employing thefollowing conditions:

-   -   Column: RP18, 5μ, 150×4.6 mm    -   Eluent: 40% 0.05M of potassium hydrogen phosphate (K₂HPO₄)        adjusted to pH 8.2 with 20% phosphoric acid; 60% acetonitrile    -   Flow rate: 0.9 ml min⁻¹    -   Detection: UV, λ=210 nm    -   Column Temp.: 30° C.

Sample

-   -   Volume: 50 μl    -   Diluent: Same as Eluent

Sample solutions were freshly prepared from azithromycin and injected oncolumn. The percentages of impurities were calculated from theintegrator output.

Performance Evaluation

The performance of the HPLC system was tested using standardizedsolutions of AZT and DMAZT.

Example 8

Admixtures of Azithromycin and BHT

Mixtures of azithromycin and BHT were prepared using various methods ofadmixing to assess their effectiveness at inhibiting degradation ofazithromycin.

Preparative

Preparation 1 [CS Ex. 1: precipitated]

Technical grade azithromycin (10 g, 13 mmol) and BHT (0.18 g, 0.82 mmol,6.1 mole %) were dissolved in absolute ethanol (30 ml) at 20° C. in a250 ml three-necked flat flanged jacketed vessel equipped with amechanical stirrer, a condenser and thermometer. Water (3 ml) was addedat 20° C. and the solution was heated at a constant 9° C. h.sup.-1temperature gradient to 55° C. over about 4 hours. More water (11 ml)was slowly added to the vessel at between 35° C. and 55° C., whichcaused a precipitate to form. The resulting suspension was maintained at55° C. for another two hours. During this time interval more water (49ml) was added to the suspension. The suspension was then cooled at aconstant temperature gradient from 55° C. to 20° C. over 2 hours andfiltered at 20° C. After drying, a stable dry product (9 g, 90%) wasobtained.

Preparation 2 [CS Ex. 2: Added at Cloudiness]

Technical grade azithromycin (10 g, 13.35 mmol) was dissolved inabsolute ethanol (30 ml) at 20° C. in a 250 ml three-necked flat flangedjacketed vessel equipped with a mechanical stirrer, a condenser andthermometer. Water (3 ml) was added at 20° C. and the solution washeated at a constant 9° C. h⁻¹ temperature gradient to 55° C. over about4 hours. More water (11 ml) was slowly added to the vessel at between35° C. and 55° C. Azithromycin began to precipitate from the solution at46° C. BHT (0.18 g, 0.82 mmol, 6.1 mole %) was added at the first signof cloudiness. After reaching 55° C., the suspension was maintained atthat temperature for another two hours, over which time more water (49ml) was added. The suspension was then cooled at a constant 18° C. h-1temperature gradient from 55° C. to 20° C. over about 2 hours and thenfiltered at 20° C. A stable dry product (9 g, 90%) was obtained afterdrying.

Preparation 3 [CS Ex. 3: Portion Evaporated Portion Added at Cloudiness]

Technical grade azithromycin (10 g, 13 mmol), and BHT (0.12 g, 0.54mmol, 4.1 mole %) were dissolved in absolute ethanol (30 ml) at 20° C.in a 250 ml three-necked flat flanged jacketed vessel equipped with amechanical stirrer, a condenser and thermometer. The ethanol wasevaporated and the dry residue was taken up in fresh absolute ethanol(20 ml). Water (3 ml) was added at 20° C. and the solution was heated ata constant 9° C. h⁻¹ temperature gradient to 55° C. over about 4 hours.More water (11 ml) was slowly added to the vessel at between 35° C. and55° C. Azithromycin began to precipitate from the solution at 46° C. BHT(180 mg, 0.82 mmol, 6.1 mole %) was added at the first sign ofcloudiness. After reaching 55° C., the suspension was maintained at thattemperature for another two hours, over which time more water (49 ml)was added. The suspension was cooled at a constant temperature gradientof 18° C. h⁻¹ from 55.° C. to 20° C. over about 2 hours and thenfiltered at 20° C. A stable dry product (9 g, 90%) was obtained afterdrying.

Preparation 4 [Milling]

Azithromycin (1 g, 1.3 mmol) was weighed out and set aside. BHT (12 mg,0.054 mmol, 4.1 mole %) was finely milled with a mortar and pestle. Theazithromycin was added portionwise to the BHT. Each portion wasthoroughly milled with the BHT using the mortar and pestle.

Preparation 5 [Comparative]

In this example, no antioxidant was used. In other respects, theazithromycin was processed according to Preparation 1 and the resultingproduct was used as a control sample against which to compare thedegradation rates of stabilized azithromycin compositions.

Methodology

Samples of azithromycin admixtures prepared according to preparations1-5 were analyzed by HPLC for impurity content immediately after theirpreparation by mixing with an appropriate quantity of eluent to give anapproximately 4 mg/ml clear solution. Another sample of each of thepreparations was stored at 55° C. The vial contents were analyzed byHPLC seven days after being placed in the oven.

Results

The results of the accelerated stability study on stabilizedazithromycin are recorded in Table 1. TABLE 1 Comparison of Degradationof Azithromycin stabilized with BHT and without Stabilization UponExposure to 55° C. Total Impurities Total Impurities Exposure After BHTBefore Exposure Time Exposure Percent Preparation (mole %) (% Area)(Days) (% Area) Change Method of Admixing 1 6.1 0.66 7 1.16 0.50 AZT andBHT co-precipitated from solution 2 6.1 0.88 7 0.98 0.10 Precipitationof AZT from a suspension of BHT 3 4.1 0.66 7 0.86 0.20 Co-precipitationof AZT and BHT from a suspension of BHT 4 4.1 0.25 16 1.03 0.78 Milling5 — 0.27 7 3.76 3.49 No BHT was used

The four different techniques of intimately admixing azithromycin andBHT used in Preparations 1-4 led to a significant reduction in impuritycontent, relative to the control, after the admixture was subjected tooxidative stress. The stability results suggest that degradation occursby an oxidation pathway because of the general inhibition achieved byadding the free radical inhibitor BHT. The degrees of inhibitionobserved using the different techniques of admixing are significantlydifferent. Comparison of the results from Preparations 1 and 2 showsthat oxidation is inhibited somewhat more effectively by adding thestabilizer as soon as the azithromycin begins to precipitate from theethanolic solution, rather than before, but that both techniques arehighly effective. It is believed that addition of the stabilizer at thetime that the azithromycin begins to precipitate from the solution maybe more effective relative to addition of the stabilizer beforeprecipitation because the stabilizer or antioxidant (such as BHT) ismore effectively entrapped within the already formed crystals andconsequently has increased protective activity. If the crystals are notyet formed, the stabilizer or antioxidant is more easily washed out bythe solvent. Comparison of the results from Preparations 2 and 3 showsthat the anti-oxidant inhibiting effect of BHT did not diminish overtime. The best results of azithromycin stabilization were achieved byforming a stabilized azithromycin composition by co-milling ofazitbromycin and an antioxidant such as BHT.

Example 9 Admixtures of Azithromycin and Food Grade Antioxidants

The inhibiting effect of food grade antioxidants was explored at yetlower concentrations and with other mixing methods.

Preparative

Preparation 6 [M 2206]

Technical grade azithromycin was recrystallized from ethanol. Noanti-oxidants were added.

Preparation 7 [T 582-02]

Technical grade azithromycin (300 g, 400 mmol) was recrystallized fromethanol. BHT (1.2 g, 5.4 mmol, 1.4 mole %) was dissolved in ethanol andthe solution was sprayed onto the azithromycin with thorough mixing.

Preparation 8 [T 592-03]

Technical grade azithromycin (300 g, 400 mmol) was recrystallized fromethanol. BHT (1.2 g, 5.4 mmol, 1.4 mole %) and PG (1.2 g, 5.7 mmol, 1.4mole %) were dissolved in ethanol and the solution was sprayed onto theazithromycin with thorough mixing.

Preparation 9 [T 582-04]

Technical grade azithromycin (300 g, 400 mmol) was dissolved in ethanoland a solution of BHT (1.2 g, 5.4 mmol, 1.4 mole %) in ethanol wascombined with the azithromycin solution. The ethanol was then evaporatedleaving a residue of azithromycin and BHT in intimate admixture.

Preparation 10 [T 582-05]

Technical grade azithromycin (300 g, 400 mmol) was dissolved in ethanoland a solution of BHT (1.2 g, 5.4 mmol, 1.4 mole %) and PG (1.2 g, 5.7mmol, 1.4 mole %) was combined with the azithromycin solution. Theethanol was then evaporated leaving a residue of azithromycin, BHT andPG in intimate admixture.

Methodology

Preparations 6-10 were incubated at 25° C. and 50° C. for 20 hours underopen cap conditions.

Results

The results of the accelerated stability study comparing azithromycinstabilized by co-precipitation with an antioxidant and granulation withan antioxidant-containing solution are reported in Table 2. TABLE 2Comparison of Degradation of Unstabilized Azithromycin, AzithromycinStabilized by Wet Granulation with Antioxidant and AzithromycinStabilized by Co-precipitation with an Antioxidant After Twenty Hours atAmbient or Elevated Temperature Temp Antioxidant % Impurity 1 % Impurity2 % Impurity 3 % Impurity 4 Total Preparation (° C.) (mole %) (RRT^(a)≈0.23) (RRT^(a) ≈0.30) (RRT^(a) ≈0.34) (RRT^(a) ≈0.76) Impurity Methodof Mixing  6^(b) 25 — 0.07 0.19 0.09 0.03 0.38 Antioxidant was notadded. unstabilized 50 0.30 0.50 0.16 0.16 1.12 7 25 BHT (1.4^(b)) 0.070.24 0.08 0.05 0.44 Azithromycin granulated with an 50 0.32 0.52 0.220.16 1.22 ethanolic solution of antioxidant. 8 25 BHT (1.4) 0.06 0.210.06 0.04 0.37 Azithromycin granulated with an 50 & PG (1.4) 0.28 0.380.27 0.15 1.08 ethanolic solution of antioxidant. 9 25 BHT (1.4) 0.090.22 0.07 0.03 0.41 Co-precipitation of AZT and 50 0.08 0.22 0.08 0.060.44 antioxidant 10  25 BHT (1.4) 0.08 0.20 0.08 0.03 0.39Co-precipitation of AZT and 50 & PG (1.4) 0.08 0.22 0.08 0.06 0.44antioxidant^(a)RRT = relative retention time^(b)1.4 mole % corresponds to approximately 0.4 weight percent for bothBHT and PG

As can be seen by comparison of the results obtained from Preparations 9and 10 with those obtained from Preparations 6 and 7, the use ofantioxidants resulted in less degradation when the antioxidants wereco-precipitated with azithromycin versus granulating azithromycin withan ethanolic solution containing the antioxidants. Degradation of theuntreated azithromycin was most significant at elevated temperature, yetelevated temperature had little effect upon the degradation rate ofazithromycin that was coprecipitated with an antioxidant (Preparations 9and 10). In addition, the mode of application of the antioxidant is moreimportant to achieving the inhibiting effect than the amount ofantioxidant used (compare the total impurity content of Preparations 8,9 and 10 after twenty hours at 50° C.).

Example 10

Wet Granulated Tablet of Stabilized Azithromycin

In addition to studying the stability of mixtures highly concentrated inazithromycin (Le., mixtures of azithromycin and an antioxidant), westudied the stability of azithromycin in representative pharmaceuticalcompositions and dosage forms containing antioxidant mixed with AZT invarious ways.

Formulations

Formulation 1 [T 582-02]

Stabilized azithromycin resulting from Preparation 7 was formulated intoa wet granulated tablet following the stepwise procedure below using thecomponents in Table 3. TABLE 3 Per mg/ Wt. Batch No Components Tablet %(g) 1 Preparation 7 (AZT granulated 270 58.35% 219.12 with BHT soln.) 2Dibasic Calcium phosphate 30 6.48 24.28 dihydrate 3 Sodium starchglycolate 9.4 2.03 7.61 4 Sodium lauryl sulfate (SLS) 3.13 0.68 2.54 5Povidone K-25 (PVP) 19 4.11 15.36 6 Dibasic Calcium Phosphate 115 24.9092.95 Dihydrate 7 Sodium starch glycolate (SSG) 9.4 2.03 7.61 8Magnesium stearate 4.75 1.03 3.82 9 Colloidal silicon dioxide 2.09 0.451.69 (Cab-O-Sil ®) Total 462.7 100.00 347.98 10 BHT in Azithromycin:1.08 0.23 0.88 11 Alcohol 2A (removed in 40 processing)1. A solution of SLS (2.54 g) and PVP K-25 (15.36 g) was prepared indenatured alcohol formula 2A (40 g) (see USP).2. Preparation 7 (220.0 g) was mixed in a polyethylene bag with dibasiccalcium phosphate dihydrate and sodium starch glycolate.3. The product of step 2 was transferred into a Hobart planetary mixerand granulated with the PVP-SLS solution of step 1 at low speed for 1minute.4. The granulate was passed through a hand screen (#8 mesh) and dried at45° C. for 6 hours in a forced air oven.5. The dried granulate of step 4 was passed through a hand screen (# 16mesh). The loss on drying (LOD) of the granulate was 2.9% (90° C.).6. The screened granulate was additionally dried at 50° C. for 50minutes at which point LOD=1.6-1.9%.7. The dried granulation of step 6 was mixed with the dibasic calciumphosphate dihydrate and SSG in a polyethylene bag for 2 minutes.8. In a separate bag colloidal silicon dioxide was mixed with about 100g of the granulate of step 7 and then passed through a hand screen (# 16mesh) and then combined with the remaining quantity of the granulate ofstep 7 and mixed for 1 minute in a polyethylene bag.9. The magnesium stearate was combined with about 100 g of the granulateof step 8, passed through a hand screen (#16 mesh) and then combinedwith remaining quantity of step 8 and mixed for 1 minute in polyethylenebag.

Capsule-shape tablets were prepared from the granulate obtained afterstep 9 using 0.248.times.0.560 inch punches on a B3B Manesty tabletpress.

Formulation 2 [T 582-03]

Formulation 2 was prepared using the same inactive ingredients andprocessing as per Formulation 1 but substituting Preparation 8containing AZT granulated with an ethanolic solution containing 1.4 mole% of BHT and PG for Preparation 7. The formulation thus contained 0.23wt. % of each of BHT and PG.

Formulation 3 [T 582-04]

Formulation 3 was prepared using the same inactive ingredients andprocessing as per Formulation 1 but substituting Preparation 9, aco-precipitate of AZT and 1.4 mole % BHT from an ethanolic solution, forPreparation 7. The formulation thus contained 0.23 wt. % of BHT.

Formulation 4 [T 582-05]

Formulation 4 was prepared using the same inactive ingredients andprocessing as per Formulation 1 but substituting Preparation 110, aco-precipitate of AZT, 1.4 mole % BHT, and 1.4 mole % PG, from anethanolic solution, for Preparation 7. The formulation thus contained0.23 wt. % of BHT and PG.

Methodology

All tablets were stressed under “open cap” conditions at 50° C. for 184h.

Results

The results of the accelerated stability study on tablets formulatedwith stabilized azithromycin are reported in Table 4. TABLE 4 Comparisonof Stability of Wet-Granulated Tablets Containing 250 mg StabilizedAzithromycin Prepared by Different Methods of Admixing The Azithromycinand Antioxidant Upon Exposure to 50° C. Total Impurities (%) AntioxidantBefore Percent Change Formulation Preparation (Wt. % of Tablet) Exposure66 h 184 h 66 h 184 h Method of Admixing 1 7 BHT (0.23%) 0.47 1.51 2.551.04 2.08 AZT granulated with ethanolic solution containing antioxidant.2 8 BHT (0.23%) 0.37 1.20 2.10 0.83 1.73 AZT granulated with ethanolicPG (0.23%) solution containing antioxidant. 3 9 BHT (0.23%) 0.38 0.711.17 0.33 0.79 Co-precipitation of AZT and antioxidant. 4 10 BHT (0.23%)0.34 0.40 0.58 0.20 0.24 Co-precipitation of AZT and PG (0.23%)antioxidant.

The results recorded in Table 4 show that an intimate admixture of AZTand antioxidant obtained by co-precipitation is more effective atinhibiting degradation in a wet granulated tablet formulation than theapplication of the antioxidant during wet granulation of the AZT withother excipients.

Example 11

Azithromycin Tablet Prepared by Dry Granulation

The stability of dry granulated tablet formulations of azithromycin thatwere pre-compressed by roller compaction was also assessed informulations with and without an added food grade antioxidant.

Formulations

Azithromycin was formulated into dry granulated 500 mg tablets followingthe stepwise procedure below using the excipients in Table 5. TABLE 5Formulations (mg/Tablet) Stage Ingredients 5 6 7 8 9 Part I Azithromycin525.3* 525.3* 525.3* 525.3* 525.3* Colloidal SiO₂ (Aerosil 200 ®) 8.08.0 8.0 8.0 8.0 Propyl Gallate — 0.8 — — — BHT — 0.8 — 0.4 0.8 SodiumAscorbate — — 1.6 — — Part II Dibasic Calcium Phosphate 90.7 89.1 89.190.3 89.9 Pregelatinized Starch 55.0 55.0 55.0 55.0 55.0 CroscarmelloseSodium 18.0 18.0 18.0 18.0 18.0 Talc 32.0 32.0 32.0 32.0 32.0 MagnesiumStearate 2.0 2.0 2.0 2.0 2.0 Part III Colloidal SiO₂ (Aerosil 200 ®)10.0 10.0 10.0 10.0 10.0 Sodium Lauryl Sulfate 2.4 2.4 2.4 2.4 2.4Croscarmellose Sodium 28.0 28.0 28.0 28.0 28.0 Talc 13.6 13.6 13.6 13.613.6 Magnesium Stearate 15.0 15.0 15.0 15.0 15.0 Coating Opadry ® 24.024.0 24.0 24.0 24.0 Theoretical End Weight 824.0 824.0 824.0 824.0 824.0*525.3 mg of Azithromycin solvate is equivalent to 500 mg Azithromycin(based on the specific APl potency of the particular lot used)Formulation 5 [K-28201]1. Part I materials were blended in a polyethylene bag and passedthrough an oscillating granulator (Frewitt®) equipped with a 1 mmaperture screen and loaded into a twin shelled Y-cone dry blender.2. Part II materials were added to the Y-cone blender and mixed.3. The mix was passed through a roller compactor.4. The compact was twice passed through the oscillating granulator. Inthe first pass, the granulator was equipped with a 2 mm aperture screen.In the second pass, the granulator was equipped with a 1 mm aperturescreen. The milled granulate was loaded into a Y-cone blender.5. The Part III materials were added to the Y-cone blender and mixed.6. Oval tablets 9×17 mm were pressed from the mixture on a Kilian RLSrotary tablet press.7. A portion of the compressed tablets were coated with Opadry® IIWhite. This formulation did not contain stabilizers.Formulation 6 [K-28202]

Formulation 6 was processed using the same inactive ingredients andprocessing as per Formulation 5 except that 0.8 mg/tablet BHT and 0.8mg/tablet PG were added in Step 1 and the amount of dibasic calciumphosphate used was reduced to give a tablet of identical theoretical endweight. Formulation 6 contained 0.1 wt. % BHT and 0.1 wt. % PropylGallate.

Formulation 7 [K-28483]

1. Part I materials were blended in a Diosna® P-10 high shear mixer.

2. Part II materials were added to the mixer and mixed.

3. The mix was passed through a roller compactor.

4. The compact was twice passed through a Frewitt. In the first pass,the Frewitt was equipped with a 2 mm aperture screen. In the secondpass, the Frewitt was equipped with a 1 mm aperture screen. The milledgranulate was loaded into a Y-cone blender.

5. The Part III materials were added to the Y-cone blender and mixed.

6. Oval tablets 9.times.17 mm were pressed from the mixture on a KilianRLS rotary tablet press.

7. A portion of the compressed tablets were coated with Opadry® IIWhite. The formulation contained 0.2 wt. % of Sodium Ascorbate.

Formulation 8 [K-28484]

Formulation 8 was processed using the same inactive ingredients andprocessing as per Formulation 7 except that 0.4 mg/tablet BHT was addedto the Part I materials in lieu of 1.6 mg/tablet sodium ascorbate andthe amount of dibasic calcium phosphate was adjusted to yield a tabletof identical weight. Formulation 8 contained 0.05 wt. % of BHT.

Formulation 9 [K-28485]

Formulation 9 was processed using the same inactive ingredients andprocessing as per Formulation 8 except that 0.8 mg/tablet BHT was addedin Step I and the amount of dibasic calcium phosphate was reduced by 0.4mg/tablet. Formulation 9 contained 0.1 wt. % of BHT.

Methodology

Tablets were stressed under a variety of storage conditions: in blisterpacks, in high density polyethylene (HDPE) bottles, and in aluminumlaminated bags. The containers were filled and then sealed underordinary atmosphere. The tablets were stored for five or seven days at55° C.

Results

The results of the accelerated stability study on tablets prepared bydry granulation with pre-compression by roller compaction are reportedin Table 6. TABLE 6 Stability of Dry-Granulated 500 mg AzithromycinTablets Pre-Compressed by Roller Compaction to Storage at 55° C. inConventional Pharmaceutical Packaging and with or Without Different FoodGrade Antioxidants Formulated in the Tablets Total Impurities By HPLC (%Area) Storage Stabilizer Exposure Time Before After FormulationConditions (Wt. % of Tablet) (Days) Exposure Exposure Change 5(coated)Blister Pack — 5 0.7 1.3 0.6 5(coated) HDPE Bottle — 5 0.7 1.9 1.26(coated) Blister Pack BHT (0.1) & PG (0.1) 5 0.4 0.6 0.2 6(coated) HDPEBottle BHT (0.1) & PG (0.1) 5 0.4 0.6 0.2 7 (coated) Aluminum LaminateBag SA (0.2) 7 0.3 0.8 0.5 7 (uncoated) Aluminum Laminate Bag SA (0.2) 70.6 0.9 0.3 8 (coated) Aluminum Laminate Bag BHT (0.05) 7 0.2 0.6 0.4 8(uncoated) Aluminum Laminate Bag BHT (0.05) 7 0.4 0.7 0.3 9 (coated)Aluminum Laminate Bag BHT (0.1) 7 0.2 0.5 0.3 9 (uncoated) AluminumLaminate Bag BHT (0.1) 7 0.3 0.5 0.2

A significant reduction in the degradation rate of tablets stored inblister packs and HDPE bottles was observed when 0.2 wt. percentantioxidant was included in the formulation (compare the results forFormulations 5 and 6). BHT (alone) and mixtures of BHT and PG were moreeffective at inhibiting degradation than SA, but all three antioxidantsprovide an inhibiting effect relative to untreated azithromycin.

Example 12

Azithromycin Tablet Prepared by Dry Granulation—Slugging

The stability of dry granulated tablet formulations of azithromycin thatwere pre-compressed by slugging was also assessed with and withoutadding a food grade antioxidant to the formulation.

Formulations

Formulation 10 [T 582-08]

Formulation 10 was prepared using the same inactive ingredients asFormulation 5.

1. Part I materials were blended in a polyethylene bag and passedthrough an oscillating granulator (Frewitt®) equipped with a 1 mmaperture screen into a twin shelled Y-cone dry blender.

2. Part II materials were added to the Y-cone blender and mixed.

3. The mix was slugged into slugs using a Manesty B3B tablet press.

4. The slugs were milled in the granulator, which was equipped with a#16 mesh screen and passed into the Y-cone blender.

5. The Part III materials were added to the Y-cone blender and mixed.

6. Oval tablets 9.times.19 mm were pressed from the mixture on a ManestyB3B rotary tablet press.

7. A portion of the compressed tablets were coated with Opadry® IIWhite. Coating was performed by top spraying a suspension of Opadry II®White in a Fluidized Bed (Uniglatt®). The inlet temperature was 60° C.;the outlet temperature was 40° C. Formulation 10 did not contain anantioxidant.

Formulation 11 [T 582-09]

Formulation 11 used the same inactive ingredients as Formulation 6 andwas processed as per Formulation 10. Formulation 11 contained 0.1 wt. %BHT and 0.1 wt. % Propyl Gallate.

Methodology

Stabilized and unstabilized azithromycin tablets prepared by drygranulation with slugging were stored at 60° C. in sealed amber glassbottles for 114 h. Another bottle of stabilized azithromycin tablets wasstored “open cap” under identical conditions. Stabilized azithromycintablets were also studied at 55° C. in polypropylene (PP) and amberglass bottles.

Results

The results of the accelerated stability study on tablets formulated bydry granulation with pre-compression by slugging are recorded in Table7. TABLE 7 Comparison of Degradation of Dry-Granulated AzithromycinTablets with And Without 0.1 Wt. % BHT and 0.1 Wt. % PG at ElevatedTemperatures Storage Condition Total Impurities Detected by HPLC (%Area) Formulation Storage Container Temp. (° C.) Time (h) BeforeExposure After Exposure Change 10 Amber glass bottle 60 114 0.66 3.863.20 (unstabilized) (closed cap) 11 Amber glass bottle (open cap) 60 1140.48 1.85 1.37 11 Amber glass bottle (closed cap) 60 114 0.48 1.44 0.9611 PP bottle 55 5 0.42 0.55 0.13 (closed cap with small headspace)¹ 11PP bottle 55 5 0.42 1.16 0.74 (closed cap with large headspace)² 11amber glass bottle 55 5 0.42 0.49 0.07 (closed cap with smallheadspace)¹¹The bottle was filled with tablets.²Two Tablets were added per bottle.

The results recorded in Table 7 show that including 0.1 wt. % BHT and0.1 wt. % PG in the formulation was effective at inhibiting degradationof azithromycin tablets prepared by dry granulation with slugging. Thestabilized tablets showed a three fold reduction in degradation comparedto unstabilized tablets at 60° C. under identical closed cappedconditions. Even under open cap conditions, the stabilized tabletsunderwent less than half the degradation than unstabilized tabletsstored in a sealed bottled.

Example 13

Powder Suitable for Preparing a Liquid Suspension Dosage Form

The stability of powder formulations suitable for making liquid dosageforms like suspensions, syrups and elixirs also was assessed with andwithout adding a food grade antioxidant to the formulation.

Formulations

Azithromycin was formulated into a powder that can be constituted as aliquid oral dosage form following the stepwise procedure below using theexcipients in Table 8. TABLE 8 Formulation 12 Formulation 13 StageIngredients (mg per dose) (mg per dose) Part I Azithromycin 210.12*210.12* Aerosil 200 20.00 20.00 BHT — 0.40 Part II Xanthan Gum 6.50 6.50Klucel LF 5.00 5.00 Sodium Phosphate Tribasic 20.00 20.00 Part IIISucrose 3850.00 3850.00 Theoretical End Weight 4111.60 4112.00*210.12 mg Azithromycin is equivalent to 200 mg Azithromycin base, basedon the specific API batch potency.Formulation 12 [K-28527]1. Part I materials were passed through an 18 mesh screen and blended ina Y cone blender.2. Part II materials were added to the Y-cone blender and mixed.3. Sucrose (milled 0.8 mm screen) was added to the Y-cone blender andmixed.4. The blend was passed through Frewitt 0.8 mm screen and blended for 5minutes. Formulation 12 did not contain an antioxidant.Formulation 13 [K-28528]

Formulation 13 was prepared using the same inactive ingredients andprocessing as Formulation 12, except that 0.01 wt. % BHT was added inStep 1.

Methodology

The stability of the powder blend was studied by placing the powder inopen capped amber bottles and storing them in a vented over for sevendays. The powder also was constituted at 40 mg/ml in water in amberbottles. The bottles were capped and stored at room temperature forseven days.

Results.

The results of the accelerated stability study on the dry powder and the(unaccelerated) stability study on the solution are recorded in Table 9.TABLE 9 Comparison of Degradation of Azithromycin Powder Formulation forPreparing Liquid Dosage Forms with And Without 0.01 Wt. % BHT RRT RRTRRT RRT Total Antioxidants Time T 0.28 0.36 0.38 0.83 ImpurityFormulation (Wt. %) (days) (° C.) (%) (%) (%) (%) (%) 12 — 0 — 0.15 0.240.11 <0.1 0.50 12 (dry powder) — 7 55 0.42 0.65 0.28 0.31 1.66 % Change0.27 0.41 0.17 0.31 1.16 12 (Constituted) — 7 RT 0.10 0.19 <0.1 <0.10.50 % Change^(a) ˜0^(a)  ˜0^(a)  ˜0^(a)  ˜0^(a)  ˜0^(a)  13 — 0 — 0.100.19 <0.1 <0.1 0.29 13 (dry powder) BHT (0.01) 7 55 0.34 0.55 0.23 0.331.45 % Change 0.24 0.36 0.23 0.33 1.16 13 (Constituted) BHT (0.01) 7 RT0.12 0.20 <0.1 <0.1 0.3 % Change 0.02 0.01 0.00 0.00 0.03^(a)The impurity (identified by RRT in the above table) percentagevalues at 0 days and after 7 days (reconstituted) were of negligibledifference, indicating that essentially no degradation occurred duringstorage of the reconstituted formulation for 7 days.

The data shows that the addition of 0.01 wt. % BHT to the powderformulation for making liquid dosage forms did not improve the stabilityof azithromycin in the powder when held at 55° C. for seven days. Theresults of Formulations 12 and 13 show that, in general, no additionalstability is achieved when the antioxidant is combined with theazithromycin by simple powder mixing of the two, in contrast to formingan intimate admixture of the azithromycin and antioxidant by, e.g.,co-precipitation or co-milling as described hereinabove.

1. A container for packaging azithromycin made of gas impermeablematerial wherein after storage azithromycin degradation products do notexceed 5% by weight of the azithromycin.
 2. The container according toclaim 1, wherein after storage azithromycin degradation products do notexceed 3% by weight of azithromycin.
 3. The container according to claim1, wherein the gas impermeable material is laminated aluminum.
 4. Thecontainer according to claim 1, wherein the container comprises at leasttwo layers of gas impermeable material, wherein at least one of thoselayers is aluminum.
 5. The container according to claim 1, wherein theazithromycin is azithromycin solvate.
 6. The container according toclaim 5, wherein the azithromycin is selected from the group consistingof ethanol solvate, propanol solvate, and a hydrate.
 7. The containeraccording to claim 6, wherein the azithromycin is monohydrateazithromycin.
 8. A container for packaging azithromycin monohydrate madeof gas impermeable material wherein after storage less than about 5% ofazithromycin monohydrate is transformed to azithromycin dihydrate uponstorage of one year.
 9. The container according to claim 8, wherein thegas impermeable material is laminated aluminum.
 10. The containeraccording to claim 1, wherein the container is in the form of a bag orpouch.
 11. The container according to claim 1, wherein the gasimpermeable material is impermeable to oxygen.
 12. The containeraccording claim 1, wherein the gas impermeable is on the interior of thecontainer.
 13. The container according to claim 1, wherein theazithromycin is stored at a temperature of about 25° C. to about 55° C.14. The container according to claim 1, wherein the azithromycin isstored at 60% relative humidity.
 15. The container according to claim 1,wherein the azithromycin is stored for at least one month.
 16. Thecontainer according to claim 1, wherein the degradation products areidentified by HPLC relative to retention times of about 0.26, 0.34,0.37, or 0.80 as compared to azithromycin.
 17. A method for storingazithromycin comprising packaging azithromycin in a container comprisinga gas impermeable material wherein after storage azithromycindegradation products do not exceed 5% by weight of the azithromycin. 18.The method according to claim 17, wherein the gas impermeable materialis laminated aluminum.
 19. The method according to claim 18, wherein thecontainer comprises at least two layers of gas impermeable material,wherein at least one of those layers is laminated aluminum.
 20. A dryblend, used for forming azithromycin tablets by direct compression,comprising: (a) azithromycin obtained from the packaging of claim 1; and(b) at least one pharmaceutically acceptable excipient, wherein saidazithromycin is not azithromycin dihydrate. 21-102. (canceled)